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ERK-mediated phosphorylation of fibroblast growth factor receptor 1 on Ser777 inhibits signaling

Malgorzata Zakrzewska1, Ellen Margrethe Haugsten, Beata Nadratowska-Wesolowska

  • 1Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0310 Oslo, Norway.

Science Signaling
|February 14, 2013
PubMed

Insights

Fibroblast growth factor 1 (FGF1) signaling is regulated by a negative feedback loop. Extracellular signal-regulated kinases (ERK1/2) phosphorylate FGFR1 at Ser777, reducing FGF receptor signaling and protecting cells from overactivation.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Signal transduction

Background:

  • Fibroblast growth factor 1 (FGF1) activates cell signaling via fibroblast growth factor receptors (FGFRs).
  • FGFR activation involves tyrosine phosphorylation and downstream mitogen-activated protein kinase (MAPK) cascades.
  • FGFRs possess a serine-rich C-terminal tail crucial for regulatory mechanisms.

Purpose of the Study:

  • To elucidate a novel regulatory mechanism of FGFR signaling.
  • To investigate the role of C-terminal serine phosphorylation in FGFR1 activity.
  • To identify crosstalk mechanisms influencing FGFR signaling.

Main Methods:

  • Site-directed mutagenesis to create FGFR1 mutants (Ser777 to alanine, phosphomimetic).
  • Analysis of receptor tyrosine phosphorylation and MAPK activation.
  • Assessment of cellular responses including proliferation, migration, and axonal growth.

Main Results:

  • Phosphorylation of Ser777 in FGFR1 by ERK1 and ERK2 was identified as a key regulatory event.
  • Preventing Ser777 phosphorylation or mutating it to alanine enhanced FGF-stimulated receptor phosphorylation and downstream cellular activities.
  • A phosphomimetic mutation at Ser777 reduced FGFR1 signaling.
  • MAPK activation by other receptor tyrosine kinases led to Ser777 phosphorylation, indicating crosstalk regulation.

Conclusions:

  • A negative feedback mechanism involving Ser777 phosphorylation of FGFR1 by MAPKs (ERK1/2) controls FGF signaling.
  • This mechanism prevents excessive FGFR activation, safeguarding cellular processes.
  • The findings reveal crosstalk integration into FGFR signaling pathways.

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